36 results about "Velpatasvir" patented technology

The invention provides a novel synthesis method of hepatitis drug velpatasvir.Two intermediate compounds including a compound 4 and a compound III are utilized to synthesize the velpatasvir, the structures of the two compounds are as shown in the following formulas, wherein PG radical is t-butyloxycarboryl (Boc), carboxybenzyl (Cbz), acetyl, benzoyl or (S)-2-methoxyl acyl carbonyl amino-3-methyl-butyryl group (Moc-L-Valyl).

The invention relates to a preparation method of a Velpatasvir (GS-5816) intermediate compound which serves as a hepatitis C resisting compound and is as shown in a formula 1, as well as preparation methods of a compound as shown in a formula 3 and a compound as shown in a formula 9. The compound as shown in the formula 3 and the compound as shown in the formula 9 are used for preparing a compound as shown in a formula 2 by nucleophilic substitution under the alkaline conditions; the compound as shown in the formula 2 is used for preparing the compound as shown in the formula 1 by a coupling reaction in the presence of a metal catalyst.

The invention provides a preparation method of a velpatasvir intermediate. According to the preparation method, ortho-toluidine is taken as an initial raw material, amino acetylation protection, Friedel-Crafts acylation, deamination protection, diazotization, and bromination are adopted so as to obtain 3-bromomethyl-4-bromoacetophenone; and alkylation with 7-hydroxy-1-tetralone, intramolecular coupling, and bromination are adopted so as to obtain 9-bromo-3-(2-bromoacetyl)-10, 11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one. The yield and the purity of the velpatasvir intermediate preparedvia the preparation method are high, cost is low, and large size production is convenient to realize.

The invention relates to a novel method for synthesizing 9- bromine-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo [c, g] chromene-8(9h)-ketone. Cheap and available raw materials are utilized; the obtained compound can be applied to synthesis of an anti-hepatitis c medicine velpatasvir; the reaction is shown in the specification.

The invention discloses velpatasvir as well as an intermediate and a preparation method thereof. The preparation method of velpatasvir 1 provided by the invention comprises the following steps that inan organic solvent, under the condition of existence of alkali, catalysts and condensating agents, a compound 3 and MOC-L-valine take condensation reaction to obtain velpatasvir 1. The preparation method has the advantages that the reaction conditions are mild; the operation is simple and safe; specific purification equipment is not needed; the column chromatography separation operation in the aftertreatment process is avoided; the chiral isomer is easy to control; the yield is high; the chemical and optical purity of the prepared velpatasvir is greater than 99.50 percent; all impurities aresmaller than 0.10 percent; the raw material medicine standard can be reached; the cost is low; the preparation method is suitable for industrial production. The formula is shown in the description.

The invention provides a synthesis method of velpatasvir. The method comprises the following steps that reaction is performed on a compound of a structure shown as a formula (II) and a compound of a structure shown as a formula (III) to obtain a compound of a structure shown as a formula (IV); then, the compound of the structure shown as the formula (IV) is converted into the compound shown as the formula (I); the compound of the structure shown as the formula (II) and the compound of the structure shown as the formula (III) are directly subjected to carbon-hydrogen activation coupling; the generation of feature impurities in the synthesis step can be effectively avoided; meanwhile, a final product can be purified through continuous salifying crystallization; the post treatment process is simplified to a great degree; in addition, the purity of the obtained velpatasvir is greater than 99.0 percent; the maximum individual impurities are less than 0.1 percent.

The invention discloses a preparation method of velpatasvir intermediate, namely [9-bromine-3-(2-bromoacetyl)-10,11-dihydro-5H-bibenzo(c,g) chromene-8(9h)-one]. The structure of the intermediate corresponds to a formula VI as shown in the description. The method comprises the steps of by taking a compound, namely 4-bromoacetophenone as raw materials, carrying out chloromethylation, condensation, cyclization and bromination, and finally obtaining the velpatasvir intermediate of the formula VI. According to the method, the starting raw materials are cheap and easily available, the reaction conditions are mild, the rout is short, the yield is high and the preparation method is more suitable for industrial production.

The invention relates to a synthesizing method of velpatasvir. The synthesizing method has the advantages that the novel raw materials and novel intermediates are adopted, the number of reaction stepsis reduced, the usage amount of onium salt is reduced, the defects of longer reaction route, lower total yield rate and unsuitability to industrial production amplification in the synthesizing methodof the prior art are overcome, and the production cost is effectively reduced.

The invention discloses a velpatasvir intermediate as well as a preparation method and application thereof. The preparation method of a velpatasvir intermediate compound 4 provided by the invention comprises the following steps that under the protection of protection gas, in the organic solvent, a compound 5 and an oxidizing agent take oxidation reaction to obtain a compound 4. The velpatasvir isprepared from the intermediate compound 4; the reaction conditions are mild; the operation is simple and safe; specific purification equipment is not needed; the column chromatography separation operation in the aftertreatment process is avoided; the chiral isomer is easy to control; the yield is high; the chemical and optical purity of the velpatasvir prepared from the intermediate compound 4 isgreater than 99.50 percent; all impurities are smaller than 0.10 percent; the raw material medicine standard can be reached; the cost is low; the preparation method is suitable for industrial production. The formula is shown in the description.

The invention discloses a preparation method of a compound shown by formula (E), a velpatasvir intermediate shown by formula (K) and an analogue thereof. Materials adopted in the method disclosed by the invention are low-cost and easily obtained; the technological operation is simple; the intermediate and the product need not be subject to column chromatography separation; and the preparation method is suitable for industrialized mass production.

The invention relates to a new velpatasvir intermediate crystal form. Specifically, the invention discloses a polymorphic substance of the formula I compound and a preparation method thereof. The polymorphic substance has good purifying effect.

The invention discloses a method for preparing an NS5A inhibitor-Velpatasvir, wherein the method mainly comprises the five steps: 1) carrying out docking reaction on reaction initial raw materials VPM1, VPM2 and VPM3 under the catalytic action of alkali to prepare an intermediate VP1; 2) removing amino protecting groups from the intermediate VP1 by using a protecting group removing reagent to prepare an intermediate VP2; 3) carrying out cyclization on the intermediate VP2 and an amine compound to prepare an intermediate VP3; 4) carrying out a reaction on the intermediate VP3 with VPM4 under the action of a condensing agent to prepare an amide compound intermediate VP4; and 5) carrying out oxidation reaction on the intermediate VP4 under the action of an oxidizing agent to prepare Velpatasvir. The preparation process of Velpatasvir has the characteristics of simplified route, simple reaction conditions, enhanced operability and higher product yield, and is more suitable for large-scaleindustrial production.

The embodiment of the invention discloses a synthesis method of a Velpatasvir intermediate A, and further provides three novel compounds for synthesis of the intermediate A: a compound I, a compound I1 and a compound I2. The method for the synthesis of the Velpatasvir intermediate A has the characteristics of low cost, environment friendliness and suitability for industrialized production.

The invention discloses a Velpatasvir intermediate, a preparation method thereof and a preparation of Velpatasvir. The invention provides a preparation method of a Velpatasvir intermediate compound 6,which comprises the the step: performing a reaction of nucleophilic substitution on a compound 8 and a compound 7 in an organic solvent under a condition that alkali exists under the protection of protective gas, so as to obtain the compound 6. The preparation method provided by the invention is mild in reaction conditions and simple and safe in operation and does not need special purification equipment, column chromatography isolation operation in an aftertreatment process is avoided, and a chiral isomer is controlled easily; and the yield is high, the chemical and optical purity of Velpatasvir 1 prepared from the intermediate compound 6 are greater than 99.50%, and all impurities are less than 0.10%, so that the Velpatasvir 1 can reach the crude drug standard, is low in cost and is suitable for industrial production.

The invention discloses a preparation method of an anti-hepatitis C medicine Velpatasvir intermediate 10,11-dihydro-5H-benzo[d]naphtha[2,3-b]pyranone derivative which is 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one (V). The preparation method concretely comprises the following steps: carrying out coupling cyclization on a raw material 7-((2-bromo-5-chlorophenyl)oxo)-3,4-dihydronaphthalen-1(2H)-one under the action of a ligand and an alkali to synthesize 3-chloro-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one, substituting chlorine by using sodium cyanide to form cyanide, prearing an organic acid from the cyanide under the action of an alkali, processing the organic acid by a lithium methide reagent to obtain 3-acetyl-10,11-dihydro-5H-benzo[d]naphtho[2,3-b] ]pyran-8(9H)-one, and carrying out a two-step bromination reaction to obtain the anti-hepatitis C medicine Velpatasvir intermediate. The method provides a brand new synthesis route of the anti-hepatitis C medicine Velpatasvir intermediate, and has the advantages of easily controlled reaction steps, and realization of stable industrial production preparation.

The invention provides a method for re-crystallizing a key intermediate of a hepatitis C virus drug velpatasvir. Highly pure 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one is obtained, and parts of organic solvents can be recovered, so the method is economical and environmentally friendly. The method concretely includes the following steps: dissolving crude 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one in a mixed solvent containing a high-solubility organic solvent A and a low-solubility organic solvent B under a 35-70 DEG Cheating condition, precipitating crystals by a gradient cooling technology, centrifuging the obtained system, carrying out vacuum drying on the obtained wet solid at 30-70 DEG C, and performing normalpressure distillation on the obtained centrifugal mother liquor to recover the solvent B.

The invention discloses a preparation method of a benzochromene derivative shown as a formula (I). The benzochromene derivative can be taken as a synthesis intermediate of a drug such as a synthesis intermediate of Velpatasvir. Cheap and available 2-fluoro halogenated benzene is taken as a starting material, a brand-new synthetic route for preparing the benzochromene derivative is provided, the total yield of the whole reaction route is high, and the method is suitable for large-scale industrial production.

The invention discloses a new crystal form of Velpatasvir and a preparation method of the new crystal form. The structure of a compound with a formula I is shown as follows; a crystal form A of the compound with the formula I, which is prepared by the preparation method disclosed by the invention, has a good purification effect and physiochemical properties. (The formula I is shown in the description.).

The invention relates to the technical field of medicine, in particular to a synthesis method of a velpatasvir intermediate A. Proper reactants are selected for synthesis of the velpatasvir intermediate A, a linear synthesis mode is changed into a convergence synthesis mode, and the method is mild in reaction condition, simple in step, high in synthesis efficiency, environmentally friendly and beneficial to industrial production and has good application prospects and market potentials. Besides, the invention also provides an intermediate compound for synthesizing the velpatasvir intermediate A.

Disclosed are pharmaceutical compositions comprising three antiviral compounds. In particular, the pharmaceutical compositions comprise an effective amount of velpatasvir, an effective amount of sofosbuvir, and an effective amount of voxilaprevir. Also disclosed are methods of use for the pharmaceutical composition.

The invention provides two synthetic methods for a Velpatasvir key intermediate 3 and further provides a new compound I and a new compound I3 for preparing the intermediate 3. Please see the structures of the three compounds in description.

The invention relates to the technical field of medicine, in particular to a synthesis method of a velpatasvir intermediate A. Proper reactants are selected for synthesis of the velpatasvir intermediate A, a linear synthesis mode is changed into a convergence synthesis mode, and the method is mild in reaction condition, simple in step, high in synthesis efficiency, environmentally friendly and beneficial to industrial production and has good application prospects and market potentials. Besides, the invention also provides an intermediate compound for synthesizing the velpatasvir intermediate A.

The invention relates to a method for detecting velpatasvir related substances. Gradient elution can be carried out by taking a phosphoric acid aqueous solution and acetonitrile as mobile phases, andvelpatasvir can be effectively separated from the related substances.

The invention discloses a preparation method of an anti-hepatitis C medicine Velpatasvir intermediate 10,11-dihydro-5H-benzo[d]naphtha[2,3-b]pyranone derivative which is 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one (V). The preparation method concretely comprises the following steps: carrying out coupling cyclization on a raw material 7-((2-bromo-5-chlorophenyl)oxo)-3,4-dihydronaphthalen-1(2H)-one under the action of a ligand and an alkali to synthesize 3-chloro-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one, substituting chlorine by using sodium cyanide to form cyanide, prearing an organic acid from the cyanide under the action of an alkali, processing the organic acid by a lithium methide reagent to obtain 3-acetyl-10,11-dihydro-5H-benzo[d]naphtho[2,3-b] ]pyran-8(9H)-one, and carrying out a two-step bromination reaction to obtain the anti-hepatitis C medicine Velpatasvir intermediate. The method provides a brand new synthesis route of the anti-hepatitis C medicine Velpatasvir intermediate, and has the advantages of easily controlled reaction steps, and realization of stable industrial production preparation.

Disclosed is a preparation method for a compound shown by formula (E), a Velpatasvir intermediate shown by formula (K) and an analogue thereof. The method of the present invention uses inexpensive and easily available materials, and a simple process operation, without the need for separating the intermediates, the products are by column chromatography, and it is suitable for industrialized large-scale production..

The present invention relates to a preparation method of velpatasvir and its derivatives, specifically, the present invention prepares velpatasvir and its derivatives through the intermediate compound shown in the following formula (the definition of each group is as in the specification mentioned). The method has few by-products and low cost, and is suitable for industrial production of velpatasvir.

The invention provides a novel synthesis method of hepatitis drug velpatasvir.Two intermediate compounds including a compound 4 and a compound III are utilized to synthesize the velpatasvir, the structures of the two compounds are as shown in the following formulas, wherein PG radical is t-butyloxycarboryl (Boc), carboxybenzyl (Cbz), acetyl, benzoyl or (S)-2-methoxyl acyl carbonyl amino-3-methyl-butyryl group (Moc-L-Valyl).

The invention provides a method for re-crystallizing a key intermediate of a hepatitis C virus drug velpatasvir. Highly pure 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one is obtained, and parts of organic solvents can be recovered, so the method is economical and environmentally friendly. The method concretely includes the following steps: dissolving crude 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8(9H)-one in a mixed solvent containing a high-solubility organic solvent A and a low-solubility organic solvent B under a 35-70 DEG Cheating condition, precipitating crystals by a gradient cooling technology, centrifuging the obtained system, carrying out vacuum drying on the obtained wet solid at 30-70 DEG C, and performing normalpressure distillation on the obtained centrifugal mother liquor to recover the solvent B.

The invention discloses a preparation method of a benzochromene derivative shown as a formula (I). The benzochromene derivative can be taken as a synthesis intermediate of a drug such as a synthesis intermediate of Velpatasvir. Cheap and available 2-fluoro halogenated benzene is taken as a starting material, a brand-new synthetic route for preparing the benzochromene derivative is provided, the total yield of the whole reaction route is high, and the method is suitable for large-scale industrial production.